This invention relates to pharmaceutical compositions of drugs and neutralized acidic polymers that provide improved chemical and physical properties.
It is often desired to improve the aqueous concentration and bioavailability of a poorly soluble drug. Improving either the dissolution rate of the drug or the maximum concentration of drug achieved in an aqueous use environment can enhance the absorption and hence bioavailability of the drug. Further, decreasing the rate at which the concentration of drug falls from the maximum concentration to the equilibrium concentration may also improve bioavailability.
Forming a dispersion of a drug and polymer may enhance drug concentration in a use environment. For example, Curatolo, et al., EP 0 901 786 A2 disclose forming pharmaceutical spray dried amorphous dispersions of sparingly soluble drugs and the polymer hydroxypropyl methyl cellulose acetate succinate. The spray dried dispersions disclosed in Curatolo et al. provide superior aqueous concentration relative to dispersions formed from other methods and relative to the crystalline drug alone.
Similarly, others have recognized the enhancement in aqueous concentration afforded by dispersing a drug in a polymer. Nakamichi, et al., U.S. Pat. No. 5,456,923 disclose solid dispersions formed by twin-screw extrusion of low solubility drugs and various polymers, including hydroxypropyl methyl cellulose acetate succinate and hydroxypropyl methyl cellulose phalthalate, among others.
Nevertheless, dispersing a low-solubility drug in a polymer continues to present challenges. One problem encountered is that the drug and/or dispersion may not be physically stable. The amorphous drug may separate from the dispersion polymer, either as a drug-enriched amorphous phase or as a crystalline phase, thereby decreasing the concentration enhancement provided by the dispersion.
The inventors have also found that for some drugs, the drugs are not chemically stable within some dispersion polymers. In particular, the inventors have observed that for dispersions containing certain drugs and acidic polymers, the drug chemically degrades in the dispersion over time, resulting in a loss of potency and an increase in unwanted impurities.
Anderson et al., U.S. Pat. No. 5,508,276 disclose an enteric duloxetine pellet comprising a core consisting of duloxetine, an optional separating layer, and an enteric layer comprising hydroxypropyl methyl cellulose acetate succinate (HPMCAS). The HPMCAS may be partially neutralized to form a smooth, coherent enteric layer.
Hodges et al., U.S. Pat. No. 5,225,202 disclose an enteric coated composition which includes a medicament which is sensitive to a low pH environment of less than 3. The composition has an enteric coating formed of neutralized hydroxypropylmethyl cellulose acetate phthalate, plasticizer and anti-adherent.
Takeuchi, et al. Spherical Solid Dispersion Containing Amorphous Tolbutamide Embedded in Enteric Coating Polymers or Colloidal Silica Prepared by Spray-Drying Technique, Chem. Pharm. Bull. Vol. 35, pp. 3800-3806 (1987), disclose solid amorphous dispersions of tolbutamide and an enteric polymer. The drug and polymer are initially dissolved in a 2 wt % ammonia solution forming ammonium salts, but reverted to their original forms during the spray-drying process.
Nevertheless, there is still a need for pharmaceutical compositions of low-solubility drugs and polymers that have improved physical stability, chemical stability, and/or improved concentration enhancement and bioavailability.